Center PI: Malenka, Robert C. Principal Investigator (Project 2): Sdhof, Thomas/Malenka, Robert Summary Although long-term synaptic plasticity has been studied for half a century, the fundamental mechanisms that mediate process such as NMDA-receptor-dependent LTP remain largely unknown, and the biological significance of LTP is incompletely understood. Here, we propose a novel avenue to understanding LTP by focusing on our recent unexpected observation that two different postsynaptic cell-adhesion molecules, LRRTMs and neuroligins which both bind to presynaptic neurexins, are essential for normal LTP. The present project is guided by the hypothesis that understanding trans-synaptic signaling mediated by neurexin-based cell adhesion may provide insight into the coordinated structural changes and vesicular trafficking events that occur postsynaptically during LTP. Four specific aims utilizing conditional knockout mice of LRRTMs and neuroligins are proposed to test this overall hypothesis. Specific Aim 1 will examine how LRRTMs and neuroligins contribute to LTP, Specific Aim 2 will map candidate molecular interactions of LRRTMs and neuroligins that underlie their function in LTP, Specific Aim 3 will test the role of these interactions in LTP using replacement of endogenous with mutant proteins in conditional knockout mice, and Specific Aim 4 will test the behavioral significance of the function of LRRTMs and neuroligins especially in learning and memory, with the aim to develop tests of the role of LTP in memory that involve highly selective changes in only LTP. Together, these experiments will advance our understanding of the relation between trans-synaptic cell adhesion mediated by neurexins and their ligands and long-term plasticity, thus contributing not only insight into how synapses are formed and function, but also into how LTP is induced and expressed. Relevance In studying LRRTMs and neuroligins, the present project will not only shed light on how these central organizers of synapses contribute to long-term plasticity and on the mechanisms of such plasticity, but will also provide a basic understanding of the potential role of these proteins in neuropsychiatric disorders such as autism and schizophrenia to which these proteins have been linked genetically. PHS 398/2590 (Rev. 11/07) Page 1 Summary